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FLASH GENE

Symbol

ASPH

contributors: mct/npt/pgu - updated : 09-05-2016

HGNC name	aspartate beta-hydroxylase
HGNC id	757

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004318 25 - 5349 NP_004309 - 758 widely expressed among heart, placenta, skeletal muscle, kidney, and lung tissues 2015 26446257 also called ASPH-FL NM_020164 6 splicing 3287 NP_064549 26 225 only in cardiac and skeletal muscle 2015 26446257 also called ASPHIe, junctin isoform 1 NM_032466 14 splicing 3792 NP_115855 33 313 placenta, brain, heart, lung, kidney, skeletal muscle 2015 26446257 also called ASPHIc NM_032467 5 splicing 3242 NP_115856 - 210 cardiac and skeletal muscle 2015 26446257 also called ASPHId, variant 4, junctin NM_032468 15 - 3642 NP_115857 - 299 heart, brain, pancreas, placenta, lung, liver, kidney, skeletal muscle 2015 26446257 also called ASPHIb, Variant 2,junctate NM_001164750 - - 5203 NP_001158222 - 729 - 2015 26446257 NM_001164751 - - 3639 NP_001158223 - 298 - 2015 26446257 NM_001164752 - - 3582 NP_001158224 - 279 - 2015 26446257 isoform 8 targeting STIM1 to ER-plasma-membrane contacts upon Ca(2+)-store depletion NM_001164754 - - 3735 NP_001158226 - 294 - 2015 26446257 NM_001164756 - - 1712 NP_001158228 - 203 - 2015 26446257 NM_001164753 - - 3513 NP_001158225 - 256 - 2015 26446257 NM_001164755 - - 3663 NP_001158227 - 270 - 2015 26446257

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart         Digestive liver         Nervous brain         Respiratory lung         Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum cardiac     Muscular striatum skeletal

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	extended N-terminus with potential transmembrane (TM ) type II signal anchor domain directing the catalytic domain into the endoplasmic reticulum, N terminus comprising &
	8764;26 amino acids (a truncation of these AAs prevents junctional accumulation of ASPH)
	a Ca(2+)-binding EF-hand motif
	a compact C terminus catalytic domain, and Ca2+-sensing role of junctate was demonstrated after uncovering an EF-hand domain in the ER-luminal region, in its C terminus

mono polymer

monomer

HOMOLOGY

interspecies

homolog to murine Asph

intraspecies

homolog to TRDN

Homologene

FAMILY

aspartyl/asparaginyl beta-hydroxylase family

CATEGORY

enzyme , structural protein , transport carrier

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,lumen
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
text	potentially cleaved into a 56kDa protein in the lumen of ER
	with SERCA2 co-localized in the sarcoplasmic reticulum of cardiomyocytes
	intra-sarcoplasmic reticulum (SR) protein
	inserted into the membrane of the sarcoplasmic reticulum (SR) Ca(2+) store where it modifies Ca(2+) signalling in the heart and skeletal muscle

basic FUNCTION	potentially involved in divalent cation binding and protein-protein interaction for a number of vitamin K dependent proteins, like proC, F7, F9, F10, complement factors C1R, C1S
	may play an important role in the regulation of SR Ca(2+) cycling through the interaction with ATP2A2 in the murine heart
	SR membrane protein, which is part of the SR Ca(2+) release quaternary structure that also includes the ryanodine receptor, triadin and calsequestrin
	serves as a bridge between calsequestrin and the Ca(2+) release channel, ryanodine receptor
	involved in calcium homeostasis with calsquestrin, triadin, ryanodine receptor
	involved in calcium homeostasis in eukaryotic cells
	essential factor in maintaining normal cardiac Ca handling and cardiac function
	triadin and junctin are integral sarcoplasmic reticulum membrane proteins that form a macromolecular complex with the skeletal muscle ryanodine receptor (RYR1)
	has a role in maintaining sarcoplasmic reticulum Ca2+ store size in myotubes
	ASPH and TRDN each activate skeletal ryanodine receptors but ASPH alone mediates functional interactions with CASQ1
	normally acts as an activator of RYR channels at low luminal [Ca(2+)], and as an inhibitor at high luminal [Ca(2+)]
	Ca2+-sensing ER protein, and structural component of the ER-PM junctions where ORAI1 and STIM1 cluster and interact in T cells
	cell surface protein that catalyzes the hydroxylation of epidermal growth factor (EGF)-like repeats in Notch receptors and ligands
	mediates an alternative mechanism for generating localized Ca(2+) elevations within cells, promoting Ca(2+) release from internal stores recruited to phagosomes, thereby boosting phagocytosis

CELLULAR PROCESS

protein, post translation

PHYSIOLOGICAL PROCESS

text	hydroxylation of ASP or ASN in EGF-like domains of several proteins

PATHWAY

metabolism

aminoacid

signaling

a component	CASQ2, TRDN and ASPH form a protein complex that is associated with cardiac ryanodine receptor 2 (RYR2) SR Ca(2+) release channels
	forms a quaternary protein complex with the ryanodine receptor, calsequestrin, and triadin in the SR lumen of cardiac muscle
	indirect role for triadin in regulating myoplasmic Ca(2+) homeostasis and organizing the molecular complex of the triad but not in regulating skeletal-type excitation-contraction coupling
	Ca(2+)-sensing ER protein, and is a structural component of the ER-plasma membrane junctions where ORAI1 and STIM1 cluster and interact in T cells
	plays an additional role in STIM1 recruitment by defining the ER-PM junctions for clustering of ORAI1 and STIM1 in a Ca2+-dependent manner
	mediates an alternative mechanism for generating localized Ca(2+) elevations within cells, promoting Ca(2+) release from internal stores recruited to phagosomes, thereby boosting phagocytosis

INTERACTION

DNA

RNA

small molecule	metal binding,
	iron Fe2+

protein	interacting with ATP2A2 (binding of the C-terminal region of junctate (AAs 79-270) and luminal domain of ATP2A2 (AAs 70-89)
	constant interactions between CASQ2 and ASPH, regardless of the SR Ca(2+) concentration, implying that ASPH is an essential component of the CASQ2 scaffold
	ASPH is an interacting partner of ORAI1-STIM1 complex
	TRDN and ASPH are structurally related transmembrane proteins thought to be key mediators of structural and functional interactions between calsequestrin (CASQ1) and ryanodine receptor (RyRs) at the junctional sarcoplasmic reticulum
	C-terminal domain of ASPH binds to residues including the S1-S2 linker of RYR1 and N-terminal domain of ASPH binds between RYR1 residues 1078 and 2156

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

FDLAB

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in hepatocellular carcinoma constitutional     --low   may contribute to Ca(2+) cycling perturbations manifest in the failing heart constitutional     --over   leads to a severe cardiac remodeling and arrhythmias tumoral     --over   highly overexpressed in pancreatic cancer

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS